rasad meeting - critical path institute · 2017-08-08 · fda—marc walton johnson &...
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RASAD Meeting
AD Biomarkers: Regulatory Science Path March 29, 2012
Diane Stephenson Associate Director, CAMD [email protected]
Delivering on the FDA’s Critical Path Initiative
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Barratt et al., Nature Clin Pharm Therap 91(3): 380-383, 2012
Consortia for Creating Consensus
Predictive Safety Testing Consortium DRUG SAFETY Patient-Reported Outcome Consortium
DRUG EFFECTIVENESS Coalition Against Major Diseases
UNDERSTANDING DISEASES OF THE BRAIN
Polycystic Kidney Disease Consortium
NEW IMAGING TESTS Critical Path to TB Drug Regimens
TESTING DRUG COMBINATIONS
Biomarkers Patient Reported Outcomes Disease Progression Models Data Standards
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Coalition Against Major Diseases (CAMD) Accelerate the Drug Discovery Path to Advance Effective Treatments for Alzheimer’s and Parkinson’s Disease
Advance drug development – “Tools”
Develop common data standards
Create public databases of pooled clinical trial data Qualify biomarkers (FDA Draft Guidance 2010)
Develop “Accepted for use” quantitative disease models
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Members and Partners
6 Nonmember participants: Academic key opinion leaders, CROs
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Biomarkers are being actively employed in AD therapeutic trials
Blennow, Nature Med 2010 16(11) 1218
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AD Biomarkers for Patient Enrichment: Prognostic Biomarker Context of Use
8 Feldman, CNS Spectr. 2008;13(3 Suppl 3):4-7
CSF biomarkers
Hansson et al., 5(3):228, 2006
Baseline hippocampal volume
Jack et al, Brain 33:3336-48, 2010
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FDA Biomarker Qualification Process
Link to new website on FDA http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ DrugDevelopmentToolsQualificationProgram/default.htm
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Goal of Regulatory Qualification
To bring novel methodologies and tools into regulated drug development studies that can be used with confidence to support decision making
FDA: “If we qualify a DDT, analytically validated measurements of it can be
relied upon to have a specific use and interpretable meaning in drug development… to expedite development of successful marketing applications.
Industry… and CDER can be confident in applying the DDT for the qualified use without the need to reconfirm the DDT’s utility”
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Consortia are the common mechanism for advancing biomarkers to the FDA
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Current status of biomarker qualifications with the FDA
Woodcock et al., Qualifying Biomarkers for use in drug development: A US Food and Drug Administration Overview. Expert Opin Med Diag 5(5): 369-72, 2011
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PSTC, safety biomarkers qualified for use in preclinical drug development
14 Nature Biotechnology, May 2010, vol 28 no 5
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Biomarker Qualification Review Process at CDER
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Woodcock et al., 2011
Review team drafts
opinion
Review team checks in discipline
reviews
BQRT leads complies
reviews into executive summary integrated
review
Regulatory briefing
scheduled
Executive summary
forwarded to office
directors
Sent to AC
Results signed by
CDER director
Sponsor receives one of the following communications:
Not qualified Qualified
Advisory Committee(AC) Required?
Executive Summary accepted?
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Themes emphasized in BQRT review
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• Context of Use • Applications in Drug Development • Measurement Science • Evidentiary Standards and Research Plan
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AD CSF Biomarker Team Members
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Alliance for Aging Research—Daniel P. Perry Alzheimer’s Association—William Thies, Maria Carrillo A.J. Simon Enterprises—Adam J. Simon ADx NeuroSciences—Hugo Vanderstichele AstraZeneca—Kathleen Gans-Brangs, Pat Patterson, Chi Ming Lee Bristol-Myers Squibb—Holly Soares, Thomas Kelleher, Robert Berman, Sue Behling, Howard Feldman*,
Anthony Johnson Critical Path Institute—Lynn Hudson, Diane Stephenson, Steven Angersbach, Denise Frank, Martha
Brumfield, Christopher Davidson, Robin Shane, Elizabeth Walker, Marietta Anthony, Steven Broadbent Eli Lilly & Company—Robert Dean, Janice Hitchcock, Peng Yu, Richard Mohs FDA—Marc Walton Johnson & Johnson—Gary Romano, Allitia DiBernardo, Jerry Novak Novartis—Richard Meibach University of California, UC Davis—Laurel Beckett, Huanli Wang University of Gothenburg—Kaj Blennow University of Pennsylvania—Leslie M. Shaw Washington University—David Holtzman, John Morris Banyon Biomarkers—Andreas Jeromin BARC Laboratories—Theresa Heath University of Arizona—Erin Ashbeck University of Antwerp—Sebastiaan Engelborghs UCSD—Paul Aisen
*presently at UBC
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Key FDA questions posed to AD CSF team
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Selection of Patient Population Define level of cognitive impairment and how this relates to biomarker Assay Performance and Biomarker Performance Characteristics precision based vs accuracy based assays cutoff values interlab variability, lot /reference standards variability Data Analysis and Interpretation define and describe confirmatory datasets concern for bias Define guidelines and SOPs to allow sponsors to use biomarker effectively for determining % enrichment
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AD Imaging Biomarker Team Members
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Alliance for Aging Research—Daniel P. Perry Alzheimer’s Association—William Thies, Maria Carrillo AstraZeneca—Kathleen Gans-Brangs, Patricia Patterson Bristol-Myers Squibb—Thomas Kelleher, Feng Luo, Wendy Hayes, Holly Soares, Sue Behling, Anthony Johnson,
Howard Feldman* Critical Path Institute—Lynn Hudson, Diane Stephenson, Steven Angersbach, Denise Frank, Martha Brumfield,
Christopher Davidson, Robin Shane, Elizabeth Walker, Marietta Anthony, Steven Broadbent Eli Lilly & Company—Peng Yu, Adam Schwarz, Richard Mohs FDA—Marc Walton Imagepace—Patricia E. Cole Imperial College London—Robin Wolz IRCCS-FBF—Giovanni Frisoni, Martina Bocchetta, Marina Boccardi IXICO Ltd—Derek Hill, Paula Munday Johnson & Johnson—Gerald Novak, Gary Romano Mayo Clinic—Clifford R. Jack Novartis—Richard Meibach, Paul Maguire Pfizer—David Raunig** Synarc, Inc—Joyce Suhy, Joonmi Oh University of Arizona—Erin Ashbeck University of California, UC Davis—Laurel Beckett, Huanli Wang University of California, San Diego—James Brewer, Paul Aisen University College London—Nick Fox Kings College London—Andy Simmons, Simon Lovestone
presently at *UBC **Icon Medical Imaging
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Key questions posed by FDA to AD imaging team
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Selection of Patient Population Define level of cognitive impairment and how this relates to biomarker specificity of the biomarker to AD Assay Methodology and Biomarker Performance Characteristics test retest reliability (scanners, field strength) hippocampal volume cutoff values-how to define defining hippocampal boundaries image analysis approaches vs manual tracing of hippocampus Data Analysis and Interpretation define and describe confirmatory datasets concern for bias Define guidelines and SOPs to allow sponsors to use biomarker effectively for determining % enrichment
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Next Steps for CAMD AD Biomarker teams
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• AD biomarker teams to provide written responses to FDA questions (2 months) • Teams analyze confirmatory datasets and conduct validation studies and submit to FDA ( 6 months) • Seek advice from FDA
• Prepare and submit qualification dossier
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EMA vs FDA biomarker qualification processes
EMA • Fees charged • Accelerated review • Seeks public opinion • Evidentiary
standards - primarily literature based
• Lacks medical device division
FDA • Fees not charged • Review is slower • Does not seek public
opinion • Evidentiary
standards - prefers de novo analysis of raw data
• CDRH input/advice 22
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Summary
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• Critical Path Institute was formed to align with Critical Path Initiative and Deliver on FDA’s mission to accelerate drug development tools across the industry
• Biomarker Qualification by Regulatory Authorities is a mechanism for accelerating drug development of any novel therapeutic agent • Consortia approaches provide advantages in terms of sharing costs and
risks • EMA has qualified two AD biomarkers, CSF biochemical biomarkers and structural neuroimaging of the hippocampus for prognostic biomarker use in AD trials at the predementia stage • Two AD biomarker teams are at the consultation phase with the FDA for qualification as prognostic biomarkers for patient enrichment in AD trials at the predementia stage
~6000 Patients
• Seven companies remapped and pooled data from 22 trials for ~6100 patients: value = $400 Million
• Database open to >200 qualified research teams in 35 countries
C-Path’s Data Repository for Alzheimer’s Disease
What Was Learned? ADAS-Cog Variability
ADNI J&J Wyeth Sanofi Pfizer AstraZeneca Abbott
Item 1 Word Recall Word Recall Word Recall Word Recall Word Recall Word Recall Word Recall
Item 2 Commands Name Obj/fing. Name Obj/fing. Commands Name Obj/fing. Name Obj/fing. Name Obj/fing.
Item 3 Constr. Praxis Delayed recall Commands Constr. Praxis Commands Commands Commands
Item 4 Delayed recall Commands Constr. Praxis Delayed recall Delayed recall Constr. Praxis Constr. Praxis
Item 5 Naming Obj/fing. Constr. Praxis Idea Praxis Name Obj/fing. Constr. Praxis Idea. Praxis Idea. Praxis
Item 6 Idea. Praxis Idea Praxis Orientation Idea. Praxis Idea. Praxis Orientation Orientation
Item 7 Orientation Orientation Word Recog Orientation Orientation Word Recog Word Recog
Item 8 Word Recog. Word Recog. Remem. Instr. Word Recog Word Recog Remem. Instr. Spoken Lang Abil.
Item 9 Remem Instr. Remem Instr. Spoken Lang. Abil. Remem. Instr. Remem. Instr.
Spoken Lang. Abil. Comprehension
Item 10 Comprehension Spoken Lang. Abil.
Word Finding Dif.
Spoken Lang Abil.
Spoken Lang Abil. Word Finding Dif. Word Finding Dif.
Item 11 Word Finding Dif.
Word Finding Dif. Comprehension
Diff. Spont. Speech
Word Finding Dif. Comprehension Remem. Instr.
Item 12 Spoken Lang. Abil. Comprehension Concentration Comprehension Comprehension Concentration
Item 13 Number cancel. Concentration Concentration Concentration